ANNUAL REPORT TO CONGRESS

Federally Sponsored Research on

Gulf War Veterans Illnesses for 2000

October 2001

Research Working Group of Military and Veterans Health Coordinating Board

Annual Report to Congress 2000

Research on Gulf War Veterans Illnesses

MILITARY AND VETERANS HEALTH COORDINATING BOARD RESEARCH WORKING GROUP MEMBERS

Department of Defense:Robert E. Foster, Ph.D. Roger Gibson, D.V.M., Lt Col, USAF E. Cameron Ritchie, M.D., LTC, USA Gennady Platoff, Ph.D., COL, USA Kathleen Woody, COL, USA

Department of Veterans Affairs:John R. Feussner, M.D., M.P.H. (Chair) Kelley Ann Brix, M.D., M.P.H. Mark Brown, Ph.D. Ron Horner, Ph.D.

Department of Health and Human Services:Drue Barrett, Ph.D., CDR, USPHS M. Moiz Mumtaz, Ph.D. Janice Cordell, R.N., M.P.H. Stephen Hudock, Ph.D.

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TABLE OF CONTENTS

EXECUTIVE SUMMARY .............................................................................................. 1 INTRODUCTION ........................................................................................................... 1 RESEARCH RESULTS IN 2000 .................................................................................... 1 RESEARCH FUNDING TRENDS ................................................................................. 3 NEW RESEARCH PROJECTS AND INITIATIVES .................................................... 3 RESEARCH MANAGEMENT....................................................................................... 4 RESEARCH PRIORITIES .............................................................................................. 5

I. INTRODUCTION......................................................................................................... 6

II. RESEARCH RESULTS IN 2000................................................................................ 6 NEW RESEARCH PUBLICATIONS........................................................................................ 6 1. Symptoms and General Health Status ........................................................................ 7 2. Brain and Nervous System Function......................................................................... 15 3. Diagnosis .................................................................................................................. 22 4. Reproductive Health ................................................................................................ 23

5. Mortality ................................................................................................................... 24 6. Depleted Uranium..................................................................................................... 25 7. Chemical Weapons ................................................................................................... 26

8. Pyridostigmine Bromide ........................................................................................... 27 9. Interactions of Exposures ......................................................................................... 27

III. RESEARCH FUNDING TRENDS......................................................................... 32 A. OVERVIEW ............................................................................................................. 32 B. RESEARCH FUNDING .............................................................................................. 33 C. DIVERSITY OF RESEARCH APPROACHES................................................................. 35

IV. NEW RESEARCH PROJECTS AND INITIATIVES......................................... 36 A. NEW RESEARCH PROJECTS ........................................................................... 36 B. 2000 UPDATE OF KEY RESEARCH PROJECTS AND INITIATIVES .......... 37

V. RESEARCH MANAGEMENT ................................................................................ 45 A. OVERVIEW ............................................................................................................. 45 B. OVERSIGHT OF RESEARCH ..................................................................................... 45 C. RESEARCH COORDINATION.................................................................................... 50

VI. RESEARCH PRIORITIES .................................................................................... 53 A. RESEARCH PRIORITIES FOR 1995 ................................................................. 53 B. RESEARCH PRIORITIES FOR 1996 ................................................................. 54 C. RESEARCH PRIORITIES FOR 1998 ................................................................. 57

VII. REFERENCES........................................................................................................ 59

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EXECUTIVE SUMMARY

I. INTRODUCTION

The Secretary of Veterans Affairs is required to submit to the Senate and House Veterans Affairs Committees an annual report on the results, status, and priorities of research activities related to the health consequences of military service in the Gulf War. The Research Working Group (RWG) of the Military and Veterans Health Coordinating Board (MVHCB) prepared this document, the 2000 Annual Report to Congress, which is the seventh report on research and research activities. (PGVCB, 1995a; 1996a; 1997; 1998; 1999a; 2001)

This Annual Report is divided into six sections. Section I is an introduction. Section II highlights and summarizes research progress since the last Annual Report. Section III is an analysis of the Federal Governments portfolio of research on Gulf War veterans illnesses. Section IV highlights significant new research projects and initiatives since the last Annual Report. Section V discusses the management of Federal Gulf War veterans illnesses research programs, including research oversight, peer review, and coordination. Section VI discusses priorities established in 1995, 1996, and 1998 for future research, and highlights the progress made to date.

II. RESEARCH RESULTS IN 2000

In the past year, several research studies have yielded results that provide new and expanded information on the health problems of Gulf War veterans. Section II provides brief summaries of research projects for which results were published from January 2000 to January 2001. The RWG tracks all Federally funded research projects related to Gulf War veterans illnesses. As in previous reports to Congress, the research reports summarized in Section II are grouped according to nine focus areas: symptoms and general health status, brain and nervous system function, diagnosis, reproductive health, mortality, depleted uranium, chemical weapons, pyridostigmine bromide, and interactions of exposures.

1. Symptoms and General Health Status:

Nine large studies were published that focused on symptoms and general health. (Kang, et al, 2000; Doebbeling, et al, 2000; Knoke, et al, 2000; Bell, et al, 2000; Nisenbaum, et al, 2000; Ismail, et al, 2000; Hotopf, et al, 2000; Steele, 2000; Smith, et al, 2000) These publications included the results of studies conducted at four large research centers in Washington, DC, Iowa, San Diego, and London, UK. Each of the nine studies included several hundred to thousands of individuals. Four of the studies have included some form of medical evaluation, such as causes of hospitalization. (Knoke, et al, 2000; Bell, et al, 2000; Nisenbaum, et al, 2000; Smith, et al, 2000) Six of these studies were population-based, which means that the results of these studies may have implications for the overall population of 697,000 Gulf War veterans. (Kang, et al, 2000; Doebbeling, et al, 2000; Bell, et al, 2000; Ismail, et al, 2000; Hotopf, et al, 2000; Smith, et al, 2000)

One of the most significant conclusions based on these recent studies and others is that Gulf War veterans do not suffer from a unique, previously unrecognized syndrome. Four large studies have evaluated the health of thousands of Gulf War veterans and non-deployed veterans, involving the US Air Force; US Navy; US Army, Navy, and Air Force, combined; and all three services from the United Kingdom, combined. (Fukuda, et al, 1998; Knoke, et al, 2000; Doebbeling, et al, 2000; Ismail, et al, 1999) In each study, the patterns of symptoms reported by Gulf War veterans were similar to the patterns of symptoms reported by non-deployed veterans.

2. Brain and Nervous System Function:

Seven studies were published that focused on brain and nervous system function, including posttraumatic stress disorder, major depression, and neuropsychological functioning. (Storzbach, et al, 2000; Storzbach, et al, 2001; King, et al, 2000; Sharkansky, et al, 2000; Benotsch, et al, 2000; Fiedler, et al, 2000; Engel, et al, 2000) These publications presented the results of studies conducted at five federally funded research centers in Portland, Oregon, Boston, New Orleans, East Orange, New Jersey, and Washington, DC. Six of these studies included several hundred to several thousand individuals. Four of these publications relied upon neurological and/or psychiatric evaluations, rather than relying solely on self-administered

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surveys. (Storzbach, et al, 2000; Storzbach, et al, 2001; Fiedler, et al, 2000; Engel, et al, 2000)

Two of these seven studies, which focused on brain and nervous system function, were published by the Portland Environmental Hazards Research Center. 241 Gulf War veterans who reported unexplained symptoms, which could not be diagnosed after a thorough evaluation, were compared with 113 healthy Gulf War veterans (controls). (Storzbach, et al, 2000) 87% of the 241 cases had unexplained cognitive or psychological symptoms, 38% had unexplained musculoskeletal symptoms, and 42% had unexplained fatigue. There were 12 psychological tests and 6 neurobehavioral tests. Cases differed significantly from controls on all psychological test scales, in the direction of increased distress. Case performance on all neurobehavioral tests was deficient compared to the controls. However, the deficiencies were statistically significant in only 2 of the 6 tests. The performance of about 90% of the cases on the neurobehavioral tests was similar to the controls. (Storzbach, et al, 2001) In contrast, about 10% of the cases performed significantly worse than the controls on almost all the neurobehavioral tests.

3. Diagnosis:

Two studies were published that focused on the diagnosis of infectious diseases in Gulf War veterans, including one study on Mycoplasma fermentans, and one study on infectious diseases that are endemic to the Persian Gulf region. (Lo, et al, 2000; Specht, et al, 2000) The prevalence of antibodies to Mycoplasma fermentans was compared among chronically ill Gulf War veterans (cases) and healthy Gulf War veterans (controls), based on specimens obtained before and after the war. (Lo, et al, 2000) Some scientists and veterans have proposed that previously undetected infections with this organism might be a cause of symptoms in some Gulf War veterans. Before the war, 34 out of 718 cases (4.8%) and 116 out of 2,233 controls (5.2%) tested positive for antibodies to Mycoplasma fermentans. After the war, an additional 1.1% of cases and 1.2% of controls tested positive for antibodies. These results provided no evidence that infection with this organism was associated with the development of chronic illnesses in the cases.

4. Reproductive Health:

Two studies were published that focused on reproductive health among Gulf War veterans. These included one study on the prevalence of major congenital abnormalities among infants of veterans in Hawaii, and one study on the rates of abnormalities in cervical cytology among women veterans. (Araneta, et al, 2000; Frommelt, et al, 2000) Between 1989 and 1993, 17,182 infants were born to military parents in Hawaii, including 22% Gulf War veterans and 78% non-deployed veterans. (Araneta, et al, 2000) There were no differences in infants born to the two groups of veterans in the rates of low birth weight or prematurity. 367 infants were identified with one or more of 48 major birth defects (2% of live births). The prevalence of birth defects was similar for infants born to the two veteran groups, in the prewar and postwar periods.

5. Mortality:

One study was published that focused on mortality of Gulf War veterans in the United Kingdom. (Macfarlane, et al, 2000) The rates of mortality in all 53,462 British Gulf War veterans were compared with the rates among the same number of non-deployed British veterans. There were 395 deaths among Gulf War veterans (0.7%) and 378 deaths among non-deployed veterans (0.7%). Mortality rates due to diseases (natural causes) were slightly lower among Gulf War veterans. Mortality rates due to external causes were slightly higher among Gulf war veterans, mostly due to motor vehicle accidents. These British results are very similar to results of a mortality study in US Gulf war veterans. (Kang and Bullman, 1996) Both the UK and US mortality studies will continue indefinitely.

6. Depleted Uranium:

One study was published that focused on the effects of depleted uranium (DU) in Gulf War veterans. (McDiarmid, et al, 2001) VA and DoD initiated a national effort in August 1998 to offer a DU medical evaluation to any concerned Gulf War veteran. This study described the results of the first 169 veterans who volunteered for this program through December 1999. Of the 169 veterans who submitted 24-hour samples for determination of urinary uranium concentration, there were only 3 individuals with validated, elevated results. One of these individuals

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probably had retained DU metal fragments from a friendly fire incident. The sources of the elevated results in the other 2 persons were unknown. The authors concluded Those with normal uranium values now are unlikely to develop any uranium-related toxicity in the future regardless of what their DU exposure may have been during the Gulf War.

7. Chemical Weapons:

Three studies were published that focused on the effects of chemical weapons in laboratory animals. These studies focused on sarin, and included one study in guinea pigs and two studies in rats. (Spruit, et al, 2000; Khan, et al, 2000; Jones, et al, 2000)

8. Pyridostigmine Bromide:

One study was published that focused on the effects of pyridostigmine bromide in rats. (Li, et al, 2000)

9. Interactions of Exposures:

Nine animal studies were published that focused on the health effects of interactions of exposures. These included five animal studies of the effects of pyridostigmine bromide (PB), in combination with stressors (forced swimming stress, heat stress, severe cold stress, restraint stress, or exercise training). (Grauer, et al, 2000; Sinton, et al, 2000; Servatius, et al, 2000; Somani, et al, 2000; Verma-Ahuja, et al, 2000) Four animal studies evaluated the effects of PB, in combination with other chemicals, in particular, DEET or permethrin. (Hoy, et al, 2000a; Hoy, et al, 2000b; van Haaren, et al, 2000; Chaney, et al, 2000)

III. RESEARCH FUNDING TRENDS

The Gulf War Veterans Illnesses research portfolio currently includes 193 projects. It was last updated during the second quarter of Fiscal Year 2001 (through March 31, 2001). These 193 Federal research projects are sponsored by the Departments of Veterans Affairs (VA), Defense (DoD), or Health and Human Services (HHS). The scope of the Federal research portfolio is broad, from small pilot studies to large-scale epidemiology studies involving large populations and major research center programs. Currently,

the Federal Government is projecting cumulative expenditures of $173.6 million for research from FY 1994 through FY 2001. As of March 31, 2001, 116 projects were completed and 77 projects were ongoing. The overall emphasis of research has been greatest in the focus areas of Symptoms and General Health Status, and Brain and Nervous System Function. The numbers of projects in each focus area are examined in more detail in Section III.

IV. NEW RESEARCH PROJECTS AND INITIATIVES

Besides new research findings appearing in the published scientific literature, there have been several important events since last years Annual Report to Congress that deserve discussion. These include the awarding of new research projects and the development of new research initiatives. This section also updates important accomplishments in 2000 for key research projects and initiatives.

IV.A. NEW RESEARCH PROJECTS

IV.A.1. New Projects Funded by the 2000 DoD Broad Agency Announcements

In 1998, DoD established new funding for programmed research. The purpose of this program element funding is to address Gulf War veterans illnesses issues, which may also be of concern in future deployments. This planned funding is approximately $20 million per year for FY 1999 through FY 2002 and $5 million per year thereafter. DoD published four Broad Agency Announcements (BAAs) in 2000. The new projects funded by these BAAs will be announced in 2001. The specific requests focused on the following areas of research interest:

Epidemiological Investigations of Deployment Health Monitoring Methods

Deployment Stress Health and Performance Consequences

Biochemical and Physiological Markers to Assess Toxic Chemical Exposures and Health Effects in Deployed Military Personnel

Toxicity of Militarily Relevant Heavy Metals

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IV.B. 2000 UPDATE OF KEY RESEARCH PROJECTS AND INITIATIVES

IV.B.1. Institute of Medicine Study of Health Effects Associated with the Gulf War

In 1998, the VA contracted with the Institute of Medicine (IOM) to perform a review of the scientific and medical literature regarding adverse health effects associated with the exposures experienced during the Gulf War. The first phase of this study focused on the medical literature on pyridostigmine bromide, depleted uranium, sarin and cyclosarin, and the anthrax and botulinum toxoid vaccines. A report on this first phase was published in September 2000, entitled Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines. (IOM, 2000) The findings and research recommendations in this IOM report are summarized in Section IV.B.1. In 2000, planning started for the second phase of the IOM project, which will focus on a review of the scientific literature on pesticides and solvents used during the Gulf War.

IV.B.2. White House Report: Health Consequences of the Gulf War: An Ongoing Analysis

In mid-2000, White House staff requested that an interagency report be coordinated and edited by the MVHCB, which would summarize the activities of the Federal Government to address illnesses in Gulf War veterans. This report was completed in December 2000, and was entitled Health Consequences of the Gulf War: An Ongoing Analysis. (White House, 2000) This report provides an overview of the clinical programs, research and investigations, compensation initiatives, outreach efforts, and lessons learned. The report includes a chapter on Research, which summarizes the findings to date. The major research conclusions are provided in Section IV.B.2.

IV.B.3. Conference on Federally Sponsored Gulf War Veterans Illnesses Research

The RWG organized and hosted an international meeting, entitled 2001 Conference on Illnesses among Gulf War Veterans: A Decade of Scientific Research, on January 24-26, 2001, in Alexandria, Virginia. The purpose of the

meeting was to bring together Federally sponsored researchers on Gulf War veterans illnesses in a common forum. This was the fifth such conference, and almost 400 scientists, clinicians, government officials, and veterans attended it. The Proceedings for this conference were published in early 2001. (MVHCB, 2001b)

V. RESEARCH MANAGEMENT

The RWG has accomplished several notable achievements, including:

Development, production, and dissemination of the 1995 A Working Plan for Research on Persian Gulf Veterans Illness (PGVCB, 1995b), and its 1996 revision (PGVCB, 1996b).

Production and dissemination of Annual Reports to Congress for 1994 through 2000 on results, status, and priorities of Federal research activities (PGVCB, 1995a; 1996a; 1997; 1998a; 1999a; 2001; MVHCB, 2001a).

Secondary programmatic review and recommendations on research proposals that have been competitively reviewed by funding agencies.

Organization of five conferences of Federally funded researchers, including publication of three Proceedings (PGVCB, 1998b; PGVCB, 1999b; MVHCB, 2001b).

Coordination and oversight of implementation of relevant recommendations of the Institute of Medicine, Presidential Advisory Committee, Senate Veterans Affairs Committee, the Presidential Review Directive 5, and the Presidential Special Oversight Board (IOM, 1995, 1996; PAC, 1996a, 1996b, 1997; SVAC, 1998; NSTC, 1998; PSOB, 2000).

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Two national treatment trials (exercise/behavior therapy trial and antibiotic treatment trial).

VI. RESEARCH PRIORITIES

The RWG has identified three sets of research priorities in 1995, 1996, and 1998 (PGVCB, 1995b; PGVCB, 1996b; PGVCB, 1999a). Substantial progress has been made on each of these sets of priorities, which is detailed in Section VI.

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I. INTRODUCTION

On August 31, 1993, in response to Section 707 of Public Law 102-585, President William J. Clinton named the Secretary of Veterans Affairs (VA) to coordinate research activities undertaken or funded by the Executive Branch of the Federal Government into the health consequences of service in the Gulf War. Section 104 of Public Law 105-368 (1998) expanded the range of activities to be coordinated. VA carries out its research-coordinating role through the Research Working Group (RWG) of the Military and Veterans Health Coordinating Board (MVHCB). The Secretaries of the Department of Defense (DoD), Health and Human Services (HHS), and VA chair the MVHCB.

As part of its coordination role, VA is required to submit an annual report on the results, status, and priorities of research activities to the Senate and House Veterans Affairs Committees. This document, the 2000 Annual Report to Congress, is the seventh report on research and research activities. (PGVCB, 1995a; 1996a; 1997; 1998; 1999a; 2001) The 2000 Annual Report to Congress reports on research funded by Federal and non-federal institutions. All new peer reviewed reports of high quality research add to and build upon existing knowledge, regardless of funding source.

This Annual Report is divided into six Sections. Following this introductory Section, Section II highlights and summarizes research progress since the last Annual Report. Section III is an analysis of the Federal Governments portfolio of research on Gulf War veterans illnesses. Section IV highlights significant new research projects and initiatives since the last Annual Report. Section V discusses the management of Federal Gulf War veterans illnesses research programs, including research oversight, peer review, and coordination. Section VI discusses priorities established in 1995, 1996, and 1998 for future research, and highlights the progress made to date.

II. RESEARCH RESULTS IN 2000

New Research Publications

In the past year, several research studies have yielded results that provide new and expanded information on the health problems of Gulf War

veterans. This Section provides brief summaries of research projects for which results were published from January 2000 to January 2001. Because all scientifically peer reviewed research must be considered in any future assessments of Gulf War veterans illnesses, these summaries include both Federally funded and non-federally funded research. The primary source of information on research is from the peer reviewed scientific literature. The RWG tracks all Federally funded research projects related to Gulf War veterans illnesses. These projects are described in detail in Appendix A.

It is important to note that all research studies have strengths and limitations. Among the limitations, epidemiological studies are frequently subject to a variety of biases. For example, studies that rely on self-reported symptoms and exposures are subject to recall bias, and studies that rely on self-selected cohorts (such as registry participants) are subject to selection bias. Biases can distort the magnitude of differences between cohorts and affect the strength of associations between exposures and outcomes. Other factors potentially affecting epidemiological outcomes include sample size and response rate.

Research using animal models is also subject to limitations in its applicability to a specific situation for humans. Sources of limitations include extrapolation of biological processes from one animal species to another and extrapolation of experimental dosing regimens (route of administration, amount, and duration) from animal experiments to real human exposure situations.

The presence of limitations in a particular study does not necessarily invalidate its findings or conclusions, but must be taken into account in evaluating a studys overall weight and impact. For this reason, the strengths and limitations of each of the new reports of study findings are cited as a guide for the reader.

As in previous reports to Congress, research has been categorized according to particular focus areas. The research reports summarized below are grouped according to nine focus areas: symptoms and general health status, brain and nervous system function, diagnosis, reproductive health, mortality, depleted uranium, chemical weapons, pyridostigmine bromide, and interactions of exposures. In each category, an

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overview section highlights the results of relevant reports, followed by a summary of each individual report.

A. Symptoms and General Health Status

Overview:

Nine large studies were published in 2000 that focused on symptoms and general health. These publications included the results of studies conducted at four large research centers in Washington, DC, Iowa, San Diego, and London, UK. Each of the nine studies included several hundred to thousands of individuals. Four of the studies have included some form of medical evaluation, such as causes of hospitalization. (Knoke, et al, 2000; Bell, et al, 2000; Nisenbaum, et al, 2000; Smith, et al, 2000) Six of these studies were population-based, which means that the results of these studies may have implications for the overall population of 697,000 Gulf War veterans. (Kang, et al, 2000; Doebbeling, et al, 2000; Bell, et al, 2000; Ismail, et al, 2000; Hotopf, et al, 2000; Smith, et al, 2000)

In almost all published studies, Gulf War veterans have reported significantly higher frequencies of symptoms and medical conditions, in comparison with non-deployed veterans. In contrast, the rates of objectively validated medical conditions among Gulf War veterans have generally been similar to the rates in non-deployed veterans. These patterns have been demonstrated again in the VA National Survey and in a survey of veterans in Kansas (Kang, et al, 2000; Steele, 2000)

In 1995, VA initiated a population-based, mailed survey, entitled the National Health Survey of Gulf War Era Veterans and Their Families. (Kang, et al, 2000) A total of 11,441 Gulf War veterans responded (75%), and 9,476 non-deployed veterans responded (64%). Gulf War veterans reported many chronic medical conditions significantly more frequently than the controls, such as recurrent headaches, frequent diarrhea, and arthritis. In addition, Gulf War veterans reported an increased frequency of all 48 of the 48 symptoms on the survey, compared to the controls. 7.8% of Gulf War veterans reported having been hospitalized overnight during the past year, compared with 6.4% of non-deployed veterans. However, there were no reported differences in the rates of several

serious conditions, such as cancer, coronary heart disease, stroke, diabetes, or cirrhosis of the liver. These results were consistent with other large population-based studies of Gulf War veterans in Iowa, Canada, and the United Kingdom. (Iowa, 1997; Goss Gilroy, 1998; Unwin, et al, 1999)

The state of Kansas conducted a statewide survey in 1998 to describe the prevalence and risk factors for health problems in 1,548 Gulf War veterans and 482 non-deployed veterans (65% participation rate). (Steele, 2000) This study included only veterans who had retired or separated by 1998 or who were current Reserve/National Guard members. There were 55% Reserve/National Guard in the Kansas sample, compared to 17% of all Gulf War veterans. Gulf War veterans reported significantly higher rates of 10 of 21 medical conditions that were diagnosed or treated by a physician, such as depression, arthritis, migraine headache, or posttraumatic stress disorder (PTSD). Gulf War veterans reported significantly higher rates of all 37 of 37 symptoms. Notably, there were no reported differences in the rates of hospitalizations (1991 to 1998) or rates of application for VA disability benefits (1991 to 1998). The prevalence of the Centers for Disease Control and Prevention (CDC) working case definition of multisymptom illness was also evaluated. (Fukuda, et al, 1998) This CDC case definition was reported by 47% of Gulf War veterans in Kansas and 20% of non-deployed veterans. Overall, the Kansas data indicated that Gulf War veterans and non-deployed veterans reported similar patterns of symptoms, although Gulf War veterans reported higher rates.

Four major studies have been published that used a statistical technique, factor analysis, to identify patterns of symptoms. The health of thousands of Gulf War veterans has been evaluated in these four studies, involving the US Air Force; the US Navy; the US Army, Navy, and Air Force combined; and all three armed services in the United Kingdom, combined. (Fukuda, et al, 1998; Knoke, et al, 2000; Doebbeling, et al, 2000; Ismail, et al, 1999) In each of these studies, the patterns of symptoms reported by Gulf War veterans were similar to the patterns reported by non-deployed veterans. The results of these four studies are consistent with the conclusion of a recent Institute of Medicine report, which was, Thus far, there is insufficient

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evidence to classify veterans symptoms as a new syndrome. . . All Gulf War veterans do not experience the same array of symptoms. Thus, the nature of the symptoms suffered by many Gulf War veterans does not point to an obvious diagnosis, etiology, or standard treatment. (Institute of Medicine, 2000)

Differences in demographic variables, health behaviors, risk-taking behaviors, and mental or physical health could influence a soldiers postwar health status. Such factors could also influence the chance of selection for deployment. 675,626 active duty Army soldiers were followed from 1980 to the beginning of the Gulf War. (Bell, et al, 2000) About 38% of these soldiers were deployed to the Gulf War. In comparison to non-deployed soldiers, Gulf War veterans were more likely to have the following characteristics: male, fewer than 5 years of time in service, younger than 25 years of age, black, single, high school education, fewer dependents, and junior enlisted rank. Deployed soldiers were more likely to be in certain military occupational specialties: infantry/gun crews, mechanical repair, or crafts workers (e.g., plumbers, metal workers). Deployed soldiers were more likely to have received hazardous duty pay before July 1990; and deployed soldiers received this hazardous duty pay more frequently for parachuting or for potential exposure to hostile fire before July 1990. Rates of hospitalizations for all injuries in military hospitals were evaluated from 1980 to August 1, 1990. The risk of hospitalization for injuries was higher among the deployed soldiers in most years. In addition, male gender, young age, less education, single marital status, less time in service, and receipt of two or more types of hazardous duty pay during one pay period were all significant predictors of prewar hospitalization for injuries. The authors concluded that postwar excess injury risk may be explained in part by a propensity for greater risk-taking, which was evident before and persisted throughout the war.

Several studies have demonstrated a significant association between demographic, lifestyle, and occupational risk factors and increased symptoms among Gulf War veterans. For example, in the VA National Survey, Gulf War veterans who were in the Army or in the Reserve/National Guard consistently reported higher rates of symptoms and medical conditions, than veterans in other services or on active-duty. (Kang, et al, 2000) In the Kansas

study, there was a significant association between increasing symptoms in multiple organ systems in Gulf War veterans, and female gender, lower household incomes, lower education, enlisted status, and service in the Army. (Steele, 2000) The CDC evaluated the association between several risk factors and a working case definition of chronic multisymptom illness in 1,002 Air Force veterans of the Gulf War. (Fukuda, et al, 1998; Nisenbaum, et al, 2000) The multisymptom illness was significantly associated with increasing age, female gender, non-white race, current smoking, and enlisted rank.

In 1997-98, a mailed survey was conducted among a randomly selected sample of 3,297 British servicemen, who had deployed to the Gulf War (70% response rate). (Unwin, et al, 1999; Ismail, et al, 2000) The authors used two physical health status measures and two mental health status measures. Physical ill health was measured as fatigue, and as a measure of multisymptom illness, based on the CDC working case definition. (Fukuda, et al, 1998) Psychological ill health was measured as psychological distress, and as a measure of post-traumatic stress reaction. There was a significant relationship between decreasing military rank and all four health outcomes. Privates were about two to three times more likely to report ill health than officers were. At the time of the survey, 57% of the Gulf War veterans had left the armed forces. Veterans who had been discharged were about two times more likely to report all four health outcomes. There was a highly significant linear trend between smoking and all four health outcomes.

Some studies have shown a significant association between reported environmental exposures and increased symptoms among Gulf War veterans, while other studies have shown no association. In the CDC study of multisymptom illness, 6% and 39% of Gulf War veterans fulfilled the case definition of severe illness and mild-to-moderate illness, respectively. (Fukuda, et al, 1998) The rates of severe and mild-to-moderate illness were significantly associated with self-reports of pyridostigmine bromide (PB) use; insect repellent use on a regular basis; and the belief that chemical or biological weapons were used against them. (Nisenbaum, et al, 2000) Severe illness was also associated with injuries during the war that required medical attention. The authors cautioned, however, that

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these self-reports of exposures could be subject to recall bias. In particular, the reports could be strongly influenced by extensive media coverage or by psychological states, such as PTSD, which were not controlled in the analysis.

In the British study of Gulf War veterans, it was hypothesized that Royal Army personnel might have been in closer geographical proximity to some of the environmental exposures implicated during the war, than Royal Navy or Royal Air Force personnel. (Ismail, et al, 2000) Nonetheless, Army personnel reported the same levels of health problems as Navy and Air Force personnel. In addition, combat troops, such as the infantry, reported the same levels of health problems as support troops, such as engineering or medical personnel. One possible explanation of this finding is that the ground war only lasted four days, whereas chemical and biological weapons were considered to be a real threat for several months and beyond the immediate geographical frontline.

A second analysis of the British Gulf War cohort focused on the relationship between ill health after the Gulf War and vaccines received before or during the conflict. (Hotopf, et al, 2000) This study used data only from veterans who reported that they still had their vaccine records (n=923; 28% of responders). The patterns of vaccines given before and during deployment were different, with more routine vaccines and fewer biological warfare vaccines given before deployment. The associations of vaccines with six health outcomes were evaluated. Multiple vaccines (defined as 5 or more vaccines) received before deployments were associated with only one of the six health outcomes (post-traumatic stress reaction). In contrast, five of the six outcomes were associated with multiple vaccines received during deployment (all but post-traumatic stress reaction). The strongest association was with the CDC case definition of multisymptom illness. The authors concluded that multiple vaccines, combined with the stress of deployment, might be associated with ill health. This study has raised a number of methodological concerns, in particular, that the restricted sample of 923 veterans who kept their vaccine records might be biased in some way. (Shaheen, 2000; Bolton, et al, 2001)

The rates of three diseases were compared among Gulf War and non-deployed veterans, due to concern among some veterans: systemic lupus

erythematosus (SLE), amyotrophic lateral sclerosis (ALS; also called Lou Gehrigs disease), and fibromyalgia (FM). (Smith, et al, 2000) This included 551,841 service members who were deployed to the Gulf War and 1,478,704 service members who were not deployed. All military hospitalization data were evaluated for the three specific diseases during the follow-up period of August 1, 1991 to July 31, 1997 (six years). There were 36 Gulf War veterans and 160 non-deployed veterans who were diagnosed with SLE (relative risk of 0.94; not significant). There were 6 Gulf War veterans and 12 non-deployed veterans who were diagnosed with ALS (relative risk of 1.66; not significant). It is noteworthy that in 2000, the VA and DoD initiated an evaluation of the rates of ALS in Gulf War and non-deployed veterans, which will include data from VA, DoD, and civilian sources. There were 239 Gulf War veterans and 621 non-deployed veterans who were diagnosed with FM (relative risk of 1.23; significantly increased). Comprehensive Clinical Evaluation Program (CCEP) participation was a strong independent risk factor for FM. In particular, CCEP participants had 26.4 times the risk of being hospitalized for FM compared with non-participants.

Symptoms and General Health Status-Individual Studies:

1. Kang, HK, Mahan, CM, Lee, KY, Magee, CA, and Murphy, FM. Illnesses among United States veterans of the Gulf War: a population-based survey of 30,000 veterans. Journal of Occupational and Environmental Medicine 2000; 42(5):491-501. (VA-2)

In 1995, VA initiated a population-based, mailed survey, entitled the National Health Survey of Gulf War Era Veterans and Their Families. (Kang, et al, 2000) The purpose of the survey was to compare the health status of a sample of 15,000 Gulf War veterans with the health status of a sample of 15,000 non-deployed veterans. Women and members of the Reserve and National Guard were over-sampled. In 1995 to 1996, 15,817 veterans responded to the mailed survey. In 1996 to 1998, an additional 5,100 responded to a supplemental telephone survey. A total of 11,441 Gulf War veterans responded (75%), and 9,476 non-deployed veterans responded (64%) (overall response rate of 70%).

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The questionnaire included various symptoms, medical diagnoses, measures of functional impairment, and potential environmental exposures. Gulf War veterans reported many chronic medical conditions significantly more frequently than the controls, such as recurrent headaches, frequent diarrhea, and arthritis. However, there were no reported differences in the rates of several serious conditions, such as cancer, coronary heart disease, stroke, diabetes, or cirrhosis of the liver. In addition, Gulf War veterans reported an increased frequency of all 48 of the 48 symptoms on the survey, compared to the controls. Members of the Reserve or National Guard consistently reported higher rates of symptoms and medical conditions, than active-duty members did. Army veterans reported higher rates than veterans of the other services did.

50.8% of Gulf War veterans reported that they had visited a clinic or seen a physician during the past year, compared to 40.5% of non-deployed veterans. 7.8% of Gulf War veterans reported having been hospitalized overnight during the past year, compared with 6.4% of non-deployed veterans. Medical records were retrieved for a small proportion of veterans (784 records of clinic visits and 105 records of hospitalizations). To the extent that records were available, the self-reported reasons for clinic visits (e.g., headaches, rash) and reasons for hospitalizations (e.g., appendicitis) correlated well with the reasons documented in the written records.

Overall, the results of this survey indicate that the self-reported health of Gulf War veterans is not as good as the self-reported health of non-deployed veterans, as measured by functional impairment, health care utilization, symptoms, and medical conditions. These results are consistent with other large population-based studies of Gulf War veterans in Iowa, Canada, and the United Kingdom. (Iowa, 1997; Goss Gilroy, 1998; Unwin, et al, 1999) The final stage of this national VA survey includes a medical evaluation of 1,000 Gulf War veterans and their families and 1,000 non-deployed veterans and their families, which will be completed in 2001.

2. Doebbeling, BN, Clarke, WR, Watson, D, Torner, JC, Woolson, RF, Voelker, MD, Barrett, DH, and Schwartz, DA. Is there a Persian Gulf War syndrome? Evidence from a large population-based survey of veterans and

nondeployed controls. American Journal of Medicine 2000; 108(9):695-704. (HHS-1) In 1995-96, a randomly selected sample of Iowa military personnel was surveyed using a telephone interview. (Iowa, 1997) A total of 1,896 Gulf War veterans and 1,799 non-deployed veterans participated (76% response rate). The Gulf War veterans came from 889 different units that had been widely distributed during the war, which reflected a broad range of geographic and environmental exposures. The objective of this study was to look for evidence of a novel illness that was unique to Gulf War veterans, and that was not seen in a comparable military population. (Doebbeling, et al, 2000) Gulf War veterans reported significantly higher rates of 123 of 137 (90%) symptoms during the past year, compared to the controls. These symptoms were related to all organ systems. The authors concluded that the increased prevalence of nearly every symptom among Gulf War veterans is difficult to explain pathophysiologically as a single condition.

A statistical technique, factor analysis, was used to identify patterns of symptoms. This technique was used separately with the symptoms of the Gulf War veterans and with the symptoms of the controls, to determine if the patterns were unique. Factor analysis identified three patterns of symptoms that correlated with each other, among the Gulf War veterans. The three patterns included: 1) joint stiffness, myalgia, polyarthralgia, numbness or tingling, headaches, and nausea; 2) feeling nervous, worrying, feeling distant or cut-off, depression, and anhedonia; and 3) anxiety attacks, a racing, pounding or skipping heart, attacks of chest pain or pressure, and attacks of sweating.

However, these three patterns were highly replicable in the controls, that is, the patterns were almost identical (convergent correlations of 0.95 to 0.98). The authors concluded that the identification of the same patterns of symptoms among both groups is not consistent with the existence of a unique Gulf War syndrome; and the results should help alleviate concern about an unexplained mystery illness.

3. Knoke, JD, Smith, TC, Gray, GC, Kaiser, KS, and Hawksworth, AW. Factor analysis of self-reported symptoms: does it identify a Gulf War syndrome? American Journal of Epidemiology 2000; 152(4):379-388. (DoD-1A)

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In 1994-95, an evaluation was performed of 98 symptoms reported by 524 Gulf War veterans and 935 non-deployed veterans, who were members of 14 Seabee commands, and who had remained on active-duty from 1991 until the time of the study. (Gray, et al, 1999a) A questionnaire assessed postwar symptoms and environmental exposures during the war, and it screened for chronic fatigue syndrome, post-traumatic stress disorder, and psychological symptoms (Hopkins Symptom Checklist). The objective of this study was to investigate the usefulness of a statistical technique, factor analysis, in characterizing a Gulf War syndrome. (Knoke, et al, 2000)

Factor analysis applied to the symptoms of Gulf War veterans yielded five patterns of symptoms. These were: three patterns of psychological symptoms that derived from the Hopkins Symptom Checklist; one pattern that suggested clinical depression; and one pattern that contained various physical symptoms that are often reported by Gulf War veterans. Factor analysis applied to non-deployed veterans yielded the same five patterns of symptoms. However, Gulf War veterans reported these patterns of symptoms with greater frequencies than the non-deployed veterans did. The authors concluded that the symptoms and illnesses of Gulf War veterans closely reflect the symptoms and illnesses reported by non-deployed veterans; Gulf War veterans simply report more of the same symptoms and illnesses. The authors concluded that factor analysis did not identify a unique Gulf War syndrome.

Some of the earliest Gulf War veterans who reported postwar morbidity were members of a Navy Reserve unit, the Naval Mobile Construction Battalion 24 (24th Seabees). In 1994, 249 members of this unit participated in a survey (41% response). Factor analysis was used to evaluate the symptoms, which yielded six patterns of symptoms. The authors of this study interpreted these six patterns to be unique Gulf War syndromes. (Haley, et al, 1997a) A major strength of the active-duty Seabee population included in the 2000 study is that they had served in the same tasks (construction work) and at the same sites as the symptomatic Reserve members in the 24th Seabees. (Gray, et al, 1999a; Knoke, et al, 2000) Four of the five symptom patterns in the 2000 study, found in both Gulf War veterans and non-deployed veterans, resembled four of the six symptom

patterns in the 1997 Haley study. The authors of the 2000 study stated that the conclusion of the 1997 Haley study regarding unique syndromes was premature and would not have been reached had a corresponding analysis on an appropriate control group been performed.

Four major studies have been published that used factor analysis to identify patterns of symptoms. The health of thousands of Gulf War veterans has been evaluated in these four studies, involving the US Air Force; the US Navy; the US Army, Navy, and Air Force combined, and all three armed services in the United Kingdom, combined. (Fukuda, et al, 1998; Knoke, et al, 2000; Doebbeling, et al, 2000; Ismail, et al, 1999) In each of these studies, the patterns of symptoms reported by Gulf War veterans were similar to the patterns reported by non-deployed veterans. The results of these four studies are consistent with the conclusion of a recent Institute of Medicine report, which was, Thus far, there is insufficient evidence to classify veterans symptoms as a new syndrome. . . All Gulf War veterans do not experience the same array of symptoms. Thus, the nature of the symptoms suffered by many Gulf War veterans does not point to an obvious diagnosis, etiology, or standard treatment. (Institute of Medicine, 2000)

4. Bell, NS, Amoroso, PJ, Williams, JO, Yore, MM, Engel, CC, Senier, L, DeMattos, AC, and Wegman, DH. Demographic, physical, and mental health factors associated with deployment of U.S. Army soldiers to the Persian Gulf. Military Medicine 2000; 165(10):762-772. (DoD-73)

The objective of this study was to describe the prewar demographic, occupational and physical health status of active duty Army soldiers who deployed to the Persian Gulf and to compare these with the same characteristics of soldiers on active duty who did not deploy. (Bell, et al, 2000) Differences in demographic variables, health behaviors, risk-taking behaviors, and mental or physical health could influence a soldiers postwar health status. Such factors could also influence the chance of selection for deployment. This study expands on previous studies, by examining a broader range of prewar health status measures for all Army soldiers on active duty during the war, followed over a longer prewar period. A total of 675,626 active duty Army soldiers were followed from 1980, or

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upon entry into the Army if they joined after 1980, to the beginning of the Gulf War. About 38% of these soldiers were deployed to the Gulf War between August 1, 1990 and June 14, 1991.

The Total Army Injury and Health Outcomes Database were used to describe the study populations demographic, health, and behavioral characteristics. In comparison to soldiers who did not deploy, Gulf War veterans were more likely to have the following characteristics: male, fewer than 5 years of time in service, younger than 25 years of age, black, single, high school education, fewer dependents, and junior enlisted rank. Deployed soldiers were more likely to be in certain military occupational specialties: infantry/gun crews, mechanical repair, or crafts workers (e.g., plumbers, metal workers). Deployed soldiers were more likely to have received hazardous duty pay before July 1990. Compared to non-deployed soldiers, deployed soldiers received this hazardous duty pay more frequently for parachuting or for potential exposure to hostile fire before July 1990.

Rates of hospitalizations in military hospitals were evaluated from 1980 to August 1, 1990, for all causes and all injuries. After adjustment for demographic and occupational factors, deployed soldiers were at slightly, but significantly, decreased risk of hospitalization for all causes, particularly in the three years before the war. This implies that the prewar health status of deployed soldiers was as good as or better than the prewar health status of non-deployed veterans. For most years between 1980 and 1990, the risk of hospitalization for injuries was higher among the deployed soldiers, even after control of potential confounders. This could imply a greater frequency of risk-taking behavior. In addition, male gender, young age, less education, single marital status, less time in service, and receipt of two or more types of hazardous duty pay during one pay period were all significant predictors of prewar hospitalization for injuries. The authors concluded that postwar excess injury risk may be explained in part by a propensity for greater risk-taking, which was evident before and persisted throughout the war.

5. Nisenbaum, R, Barrett, DH, Reyes, M, and Reeves, WC. Deployment stressors and a chronic multisymptom illness among Gulf War

veterans. Journal of Nervous and Mental Disease 2000; 188(5):259-266. (HHS-2)

The Centers for Disease and Control Prevention performed a survey of four Air Force units in 1995 to compare symptoms and risk factors among 1,155 Gulf War veterans and 2,520 non-deployed veterans. (Fukuda, et al, 1998) A working case definition of a chronic multisymptom illness was developed, which included 1 or more chronic symptoms from at least 2 of 3 categories (fatigue, mood and cognition symptoms, and musculoskeletal symptoms). The prevalence of mild-to-moderate cases and severe cases among Gulf War veterans was 39% and 6%, respectively, compared with 14% and 0.7% among non-deployed veterans. The objective of this analysis was to determine the association between the chronic multisymptom illness and self-reported stressors during the war, among 1,002 Gulf War veterans with complete data. (Nisenbaum, et al, 2000)

Increasing age, female gender, non-white race, current smoking, and enlisted rank were significantly associated with illness. Severe illness and mild-to-moderate illness were significantly associated with self-reports of pyridostigmine bromide (PB) use; insect repellent use on a regular basis; and the belief that chemical or biological weapons (CBW) were used against them. The authors categorized these risk factors as chemical stressors (PB and insect repellent) and emotional stressors (belief in use of CBW). Severe illness was also associated with injuries during the war that required medical attention. The authors categorized injuries as physical stressors.

The authors suggested that these chemical, emotional, and physical stressors might have triggered physiological and psychological stress responses, thereby impacting the health of some veterans. They cautioned, however, that the self-reports of exposures could be subject to recall bias. In particular, the reports could be strongly influenced by extensive media coverage or by psychological states, such as PTSD, which were not controlled in the analysis.

6. Ismail, K, Blatchley, N, Hotopf, M, Hull, L, Palmer, I, Unwin, C, David, A, and Wessely, S. Occupational risk factors for ill health in Gulf veterans of the United Kingdom. Journal of Epidemiology and Community Health 2000; 54(11):834-838. (DoD-39)

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In 1997-98, a mailed survey was conducted among a randomly selected sample of 3,297 British servicemen, who had deployed to the Gulf War (70% response rate). (Unwin, et al, 1999) The objective of this particular analysis was to examine whether certain military and deployment factors were associated with increased reporting of ill health in Gulf War veterans, after adjustment for potential sociodemographic confounders. (Ismail, et al, 2000) Because there is no general consensus on the definition of ill health in Gulf War veterans, the authors used two physical health status measures and two mental health status measures. Physical ill health was measured as fatigue, using the Chalder Fatigue Questionnaire, and as a multisymptom illness, based on the Centers for Disease Control and Prevention working case definition. (Fukuda, et al, 1998) Psychological ill health was measured as psychological distress, using the General Health Questionnaire-12, and as a measure of post-traumatic stress reaction.

There was a significant relationship between decreasing military rank and all four health outcomes. Privates were about two to three times more likely to report ill health than officers were. Rank may be considered as a proxy indicator for socioeconomic status, which is associated with both physical and psychological morbidity in civilian populations. At the time of the survey, 57% of the Gulf War veterans had left the armed forces. Veterans who had been discharged were about two times more likely to report all four health outcomes. Gulf War veterans who were divorced or separated were about two times more likely than married veterans to report psychological distress or post-traumatic stress reaction, which is similar to associations seen in civilian populations. There was a highly significant linear trend between smoking and all four health outcomes.

The authors hypothesized that Royal Army personnel might have been in closer geographical proximity to some of the environmental exposures implicated during the war, than Royal Navy or Royal Air Force personnel. Nonetheless, Army personnel reported the same levels of health problems as Navy and Air Force personnel. Combat troops, such as the infantry, reported the same levels of health problems as support troops, such as engineering or medical personnel. One possible

explanation is that the ground war only lasted four days, whereas chemical and biological weapons were a real threat for several months and beyond the immediate geographical frontline.

7. Hotopf, M, David, A, Hull, L, Ismail, K, Unwin, C, and Wessely, S. Role of vaccinations as risk factors for ill health in veterans of the Gulf War: cross-sectional study. British Medical Journal 2000: 320(7246):1363-1367. (DoD-39)

In 1997-98, a mailed survey was conducted among a randomly selected sample of 3,284 British servicemen, who had deployed to the Gulf War (70% response rate). (Unwin, et al, 1999) The objective of this particular analysis was to explore the relationship between ill health after the Gulf War and vaccines received before or during the conflict. (Hotopf, et al, 2000) Because recall bias can be a problem, this study only used data from veterans who reported that they still had their vaccine records (n=923; 28% of responders). The associations of vaccinations with six health outcomes were evaluated. These were: fatigue, using the Chalder Fatigue Questionnaire; multisymptom illness, based on the Centers for Disease Control and Prevention working case definition (Fukuda, et al, 1998); psychological distress, using the General Health Questionnaire-12; a measure of post-traumatic stress reaction; health perception, using the SF-36; and physical functioning, using the SF-36.

Multiple vaccines (defined as 5 or more vaccines) received before deployments were associated with only one of the six health outcomes (post-traumatic stress reaction). In contrast, five of the six outcomes were associated with multiple vaccines received during deployment (all but post-traumatic stress reaction). The strongest association was with the CDC multisymptom illness (odds ratio of 5.0). In addition, the associations were evaluated between multiple vaccinations and three atopic conditions (asthma, hay fever, and eczema or psoriasis). There were no significant associations between vaccines, before or during deployment, and these atopic conditions. Anthrax vaccination was not associated with the CDC multisymptom illness, whether given before or during deployment.

The pattern of vaccines given before deployment was different from the pattern given during deployment, with more routine vaccines and

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fewer biological warfare vaccines given before deployment. In addition, there were probably reasons why some veterans received vaccines during the war rather than before it, including, veterans who received vaccines during deployment tended to have been deployed earlier; and Army personnel were more likely to receive multiple vaccines during deployment than Navy or Air Force personnel. The authors concluded that multiple vaccines in themselves do not seem to be harmful, in that the combination of multiple vaccines before deployment seemed safe. However, multiple vaccines, combined with the stress of deployment, might be associated with ill health. The authors recommended that every effort should be made to maintain routine vaccinations during peacetime; or at least, early vaccination with as long a gap as possible before the actual stress of deployment would be prudent.

This study has raised a number of methodological concerns, in particular, that the restricted sample of 923 veterans who kept their vaccine records might be biased in some way. (Shaheen, 2000; Bolton, et al, 2001) For example, symptomatic veterans who kept their vaccine records might have discerned the study hypothesis, and therefore over-reported the vaccines they received. The authors are continuing their investigation, using a case-control design comparing healthy and ill Gulf War veterans, and relying on Ministry of Defence medical records to validate vaccine use. (Hotopf, et al, 2001)

8. Steele, L. Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. American Journal of Epidemiology 2000; 152(10):992-1002. (Not Federally funded; funded by state of Kansas)

The objective of this study was to describe the prevalence and risk factors for health problems in 1,548 Gulf War veterans, in comparison with 482 non-deployed veterans. (Steele, 2000) Telephone interviews were conducted in 1998, achieving a 65% participation rate. Veterans currently living in Kansas in 1998 were eligible if they had served on active-duty some time between August 1990 and July 1991; and if they were separated or retired from the military or currently serving in the Reserve. Note that this sampling design lead to a skewed sample that contained 55% Reserve/National Guard, which is

more than three times the proportion that served during the war (17% Reserve/National Guard). In other studies, Reserve/National Guard troops have invariably reported more symptoms than active-duty troops. (Iowa, 1997; Sharkansky, et al, 2000; Kang, et al, 2000)

47% of Gulf War veterans stated their health was worse in 1998 than in 1990, compared to 19% of non-deployed veterans. Gulf War veterans reported significantly higher rates of 10 of 21 medical conditions that were diagnosed or treated by a physician, such as depression, arthritis, migraine headache, or PTSD. Gulf War veterans reported significantly higher rates of all 37 of 37 symptoms. Notably, there were no reported differences in the rates of hospitalizations (1991 to 1998) or rates of application for VA disability benefits (1991 to 1998).

The author proposed a Kansas case definition of Gulf War Illness as the report of chronic symptoms in 3 or more of 6 domains (fatigue/sleep problems; pain symptoms; neurologic/cognitive/mood symptoms; gastrointestinal symptoms; respiratory symptoms; skin symptoms). This Kansas case definition was reported by 34% of Gulf War veterans and 8% of non-deployed veterans. The prevalence of this Kansas case definition was significantly associated with female gender, lower household incomes, lower education, enlisted status, and service in the Army. The prevalence of the CDC working case definition of multisymptom illness was also evaluated. (Fukuda, et al, 1998) This CDC case definition was reported by 47% of Gulf War veterans and 20% of non-deployed veterans. These data clearly indicate that Gulf War veterans and non-deployed veterans reported similar patterns of symptoms, although Gulf War veterans reported higher rates.

This study has substantial limitations, in particular, all the health data and most of the military data were self-reported. The author pointed out that The considerable amount of media attention given to issues surrounding Gulf War-related health problems may have generated an increased awareness of symptoms among Gulf War veterans and an increased willingness to report them. For example, 70 of the 482 veterans, whose military records did not document that they had deployed, provided a history of Gulf War service. The self-reported

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deployment information of 50 of these veterans could not be verified, and their data was excluded in the analysis.

9. Smith, TC, Gray, GC, and Knoke, JD. Is systemic lupus erythematosus, amyotrophic lateral sclerosis, or fibromyalgia associated with Persian Gulf War service? An examination of Department of Defense hospitalization data. American Journal of Epidemiology 2000; 151(11):1053-1059. (DoD-1B)

The objective of this study was to examine the association of Gulf War service with three diseases: systemic lupus erythematosus (SLE), amyotrophic lateral sclerosis (ALS; also called Lou Gehrigs disease), and fibromyalgia (FM). All regular, active-duty personnel were included, who were on active duty during the period of August 8, 1990 to July 31, 1991. This included 551,841 service members who were deployed to the Gulf War and 1,478,704 service members who were not deployed. All military hospitalization data were evaluated for the three specific diseases, during the six-year follow-up period of August 1, 1991 to July 31, 1997.

During the six-year follow-up period, 36 Gulf War veterans and 160 non-deployed veterans were diagnosed with SLE. Gulf War service was not associated with a diagnosis of SLE (relative risk = 0.94). Other factors were significantly associated with a diagnosis of SLE: female sex (relative risk = 12.12); black race (relative risk = 3.61); and increasing age (relative risk = 1.04).

During the six-year follow-up period, 6 Gulf War veterans and 12 non-deployed veterans were diagnosed with ALS. Gulf War service was not associated with a diagnosis of ALS (relative risk = 1.66). One factor that was significantly associated with a diagnosis of ALS was increasing age. It is noteworthy that in 2000, the VA and DoD initiated an evaluation of the rates of ALS in Gulf War and non-deployed veterans, which will include data from VA, DoD, and civilian sources.

During the six-year follow-up period, 239 Gulf War veterans and 621 non-deployed veterans were diagnosed with FM. Gulf War service was significantly associated with a diagnosis of FM (relative risk = 1.23). Other factors were also significantly associated with a diagnosis of FM: female sex (relative risk = 3.28); increasing age (relative risk = 1.05); and hospitalization for any

diagnosis other than FM, during the 12 months prior to the war (relative risk =1.63). Comprehensive Clinical Evaluation Program (CCEP) participation was a strong independent risk factor for FM. In particular, CCEP participants had 26.4 times the risk of being hospitalized for FM, compared with non-participants. It is important to note that symptoms of FM are being evaluated in three large Gulf War populations. These include questionnaires and physical examinations in the VA National Survey, Iowa study, and Portland study.

B. Brain and Nervous System Function

Overview:

Seven studies were published that focused on brain and nervous system function. These publications presented the results of studies conducted at five Federally funded research centers in Portland, Oregon, Boston, New Orleans, East Orange, New Jersey, and Washington, DC. Six of these studies included several hundred to several thousand individuals. Four of these publications relied upon neurological and/or psychiatric evaluations, rather than relying solely on self-administered surveys. (Storzbach, et al, 2000; Storzbach, et al, 2001; Fiedler, et al, 2000; Engel, et al, 2000)

The Portland Environmental Hazards Research Center performed a population-based case-control study of 2,022 Gulf War veterans. In this analysis, 241 Gulf War veterans who reported unexplained symptoms, which could not be diagnosed after a thorough evaluation, were compared with 113 healthy Gulf War veterans (controls). (Storzbach, et al, 2000) 87% of the cases had unexplained cognitive or psychological symptoms, 38% had unexplained musculoskeletal symptoms, and 42% had unexplained fatigue. There were 12 psychological tests and 6 neurobehavioral tests. Cases differed significantly from controls on all psychological test scales, in the direction of increased distress. There were significant differences on tests of posttraumatic stress disorder, psychiatric symptoms, and personality measures. Almost all psychological measures had effect sizes that were large. Case performance on all neurobehavioral tests was deficient compared to the controls. However, the deficiencies were statistically significant in only 2 of the 6 tests. All neurobehavioral tests had

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effect sizes that were small. The results of the neurobehavioral tests did not support a distribution-wide deficit in ill veterans. (Storzbach, et al, 2001) The performance of about 90% of the cases was similar to the controls. In contrast, about 10% of the cases performed significantly worse than the controls on almost all the neurobehavioral tests.

Ill Gulf War veterans consistently reported more combat stressors than healthy Gulf War veterans, such as deaths of unit members. This has been demonstrated in several different groups of ill veterans. These have included veterans with posttraumatic stress disorder (PTSD) (King et al, 2000; Benotsch, et al, 2000; Engel, et al, 2000); veterans with chronic fatigue syndrome (Fiedler, et al, 2000); and veterans with unexplained symptoms that could not be diagnosed after a thorough evaluation (Storzbach, et al, 2000).

In two large longitudinal studies in Boston and New Orleans, Gulf War veterans were evaluated soon after returning from the war, and again 1 to 2 years later. (King, et al, 2000; Benotsch, et al, 2000) In both cohorts, the number of reported PTSD symptoms increased significantly from Time 1 to Time 2, rather than ameliorating over time. In the Boston cohort, the number of reported depression symptoms increased significantly from Time 1 to Time 2. (King, et al, 2000) Also, in the Boston cohort, the number of reported combat stressors increased significantly from Time 1 to Time 2.

Three studies evaluated the relationship between psychological symptoms and different types of strategies for coping with combat-related stress. (Sharkansky, et al, 2000; Benotsch, et al, 2000; Fiedler, et al 2000) In other studies, efforts to deal directly with the stressor (problem-focused or approach-based coping) tended to be associated with better outcomes, compared to attempts to alleviate the emotional distress associated with the stressor or efforts to avoid the stressor (emotion-focused or avoidance-based coping).

A subgroup of 1,058 members of the Boston cohort were selected at Time 1 because they had identified a combat-related experience as their most stressful event during the Gulf War (e.g., deaths of unit members). (Sharkansky, et al, 2000) At Time 1, increased PTSD symptoms were predicted by the number of combat-related stressors, female gender, younger age,

Reserve/National Guard status, enlisted status and by proportionately greater reliance on avoidance-based coping strategies during the war. At Time 2, PTSD symptoms were predicted by PTSD symptoms at Time 1, combat exposure, Reserve/National Guard status, and intervening stressors (such as divorce or loss of a home due to a disaster, between Time 1 and Time 2). At Time 1, depression symptoms were predicted by combat exposure, female gender, and greater reliance on avoidance-based coping strategies during the war. At Time 2, depression symptoms were predicted by combat exposure, intervening stressors, and greater reliance on avoidance-based coping strategies during the war.

In the New Orleans cohort, problem solving as a positive coping strategy decreased significantly from Time 1 to Time 2, while the disadvantageous strategy of avoidance-based coping increased significantly over time. (Benotsch, et al, 2000) Both avoidance-based coping at Time 1 and decreased family cohesion at Time 1 significantly predicted PTSD symptoms at Time 2. These relationships between coping, family cohesion, and PTSD remained significant, after controlling for emotional distress at Time 1, reported number of war zone stressors, and enlisted status.

The New Jersey Environmental Hazards Research Center performed a study to compare several risk factors among 58 Gulf War veterans, who met clinical criteria for chronic fatigue syndrome (CFS), with 45 healthy Gulf War veterans. (Fiedler, et al, 2000) Veterans with CFS reported significantly more negative life events during the 6 months following the war. Veterans with CFS reported more avoidance-based coping strategies. The authors concluded that Gulf War veterans with medically unexplained fatigue could be significantly differentiated from healthy veterans, on the basis of stressors both during and since the war (e.g., combat stressors, negative life events); personality traits (e.g., neuroticism, the tendency to experience negative, distressing emotions); and avoidance-based coping strategies.

The relationship of the diagnosis of PTSD to physical symptoms was evaluated, after controlling for the possible effects of medical diagnoses and reported environmental exposures. (Engel, et al, 2000) Symptoms and diagnoses were based on the medical records of 21,232

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participants in the DoD Comprehensive Clinical Evaluation Program. Physical symptoms were determined using a 16-item checklist. Veterans diagnosed with PTSD were more likely to report each of the 16 physical symptoms. 5.2% of veterans were diagnosed with PTSD, who reported a mean of 6.7 physical symptoms. 31.4% of veterans were diagnosed with other psychological conditions, who reported a mean of 5.3 physical symptoms. 63.4% of veterans were diagnosed with non-psychological conditions, who reported a mean of 3.1 physical symptoms. The positive association between PTSD and the number of physical symptoms remained almost unchanged, even after controlling for the potentially confounding effects of other psychological diagnoses, medical diagnoses, and reported environmental exposures. The authors recommended that Clinicians should carefully consider PTSD when evaluating Gulf War veterans with vague, multiple, or medically-unexplained physical symptoms.

Brain and Nervous System Function-Individual Studies:

1. Storzbach, D, Campbell, KA, Binder, LM, McCauley, L, Anger, WK, Rohlman, DS, and Kovera, CA. Psychological differences between veterans with and without Gulf War unexplained symptoms. Psychosomatic Medicine 2000; 62(5):726-735. (VA-6)

The Portland Environmental Hazards Research Center performed a population-based case-control study, which was designed to compare Gulf War veterans, who reported unexplained symptoms that could not be diagnosed, with healthy Gulf War veterans (controls). (McCauley, et al, 1999) Cases and controls were selected from respondents to a questionnaire, which was mailed to a random sample of 2,022 Gulf War veterans who lived in Oregon or Washington. Questions focused on chronic fatigue, psychological/cognitive symptoms, and musculoskeletal symptoms. Potential cases of unexplained illnesses and healthy controls were recruited for clinical evaluations within 3 months of returning the mail questionnaire. The evaluations included a physical exam with an emphasis on neurological and musculoskeletal systems, a detailed health history, and psychological and neurobehavioral tests. Potential cases were excluded from the study if they had explainable diagnoses, or exclusionary

diagnoses, or if they denied having case symptoms at the time of clinical evaluation.

The objective of this particular analysis was to compare measures of psychological and neurobehavioral functioning between 241 Gulf War veterans with unexplained symptoms and 113 healthy Gulf War veterans. (Storzbach, et al, 2000) 87% of the cases had unexplained cognitive or psychological symptoms, 38% had unexplained musculoskeletal symptoms, and 42% had unexplained fatigue. 48% had 2 or more symptom types. There were 12 psychological tests and 6 neurobehavioral tests, which provided objective measures of memory, concentration, complex cognitive processing, and response speed.

Cases were significantly different from controls on all psychological test scales, in the direction of increased distress. There were significant differences on tests of posttraumatic stress disorder, psychiatric symptoms, and personality measures. Almost all psychological measures had effect sizes that were large. There were also significant differences on all SF-36 scales of self-rated physical health, mental health, and health-related function. Cases reported significantly greater exposure to combat stressors. Case performance on all neurobehavioral tests was deficient compared to the controls. However, the deficiencies were statistically significant in only 2 of the 6 tests (2 tests of memory, attention, and response speed). All neurobehavioral tests had effect sizes that were small.

All statistically significant psychological and neurobehavioral variables were entered as candidate variables into a logistic regression analysis, with case disposition as the dependent variable (case vs. control). Four psychological variables and no neurobehavioral variables entered into the model. The four tests were: the Hs scale of the MMPI-2, a measure of somatic symptoms associated with psychological distress; the Mississippi PTSD scale, a measure of symptoms associated with wartime posttraumatic stress; the SCIS, a measure of subjective experience of cognitive impairment; and the SF-36 General Health, a measure of perceived health. The model successfully classified 86% of the subjects overall (89% of the cases and 80% of the controls). The authors concluded that The high degree of accurate classification based on psychological tests

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highlights the relative prominence of the psychological measures, suggesting that they discriminate veterans with health symptoms from those without symptoms and should be retained as part of future batteries used to assess Gulf war veterans.

2. Storzbach, D, Rohlman, DS, Anger, WK, Binder, LM, and Campbell, KA. Neurobehavioral deficits in Persian Gulf veterans: additional evidence from a population-based study. Environmental Research 2001; 85(1):1-13. (VA-6)

The Portland Environmental Hazards Research Center performed a population-based case-control study. (McCauley, et al, 1999; Anger, et al, 1999; Storzbach, et al, 2000) The objective of this particular analysis was to compare measures of psychological and neurobehavioral functioning between 239 Gulf War veterans with unexplained symptoms and 112 healthy Gulf War veterans. (Storzbach, et al, 2001) There were 12 psychological tests and 6 neurobehavioral tests, which provided objective measures of memory, concentration, complex cognitive processing, and response speed.

There was a definite bimodal distribution on one of the neurobehavioral tests, the latency time on the Oregon Dual Task Procedure (ODTP), a test of motivation, attention, and memory. (Storzbach, et al, 2001) Subjects were divided into three groups: 30 individuals who were slow on this test (slow ODTP, including 27 cases and 3 controls); 212 other cases; and 109 controls. Both subgroups of slow ODTP and other cases had significantly higher levels of abnormal results on the psychological tests than the controls. The performance of the other cases was similar to the controls on the neurobehavioral tests, whereas, the slow ODTP subgroup performed significantly worse than the controls on almost all of the neurobehavioral tests.

On the Armed Forces Qualifying Test, which each recruit must take, there were no differences between the other cases and the controls. In contrast, the subgroup of slow ODTP had significantly lower scores on this test than the controls. This raises the possibility that the neurobehavioral performance of the slow ODTP is attributable to pre-Gulf War ability. In addition, a significantly higher percentage of slow ODTP reported seeking medical treatment

during the Gulf War (73%), than the other cases (54%) or the controls (28%). The authors suggested that this difference in seeking medical attention might mean that the slow ODTP group could have been from the unhealthy end of the Gulf War population at the time of their deployment.

The authors pointed out that deficits on neurobehavioral tests are not markers of brain dysfunction. Cognitive abnormalities are nonspecific and associated with various conditions, including somatoform disorders and PTSD. The authors concluded that their results did not support a distribution-wide neurobehavioral deficit in ill veterans. If a distribution-wide deficit had been demonstrated, it would have important implications for the understanding of Gulf War veterans with unexplained illnesses. Instead, it appeared that a small proportion of quite symptomatic veterans, who responded very slowly on a recognition memory test, also demonstrated deficits on other tests of response speed, memory and attention.

3. King, DW, King, LA, Erickson, DJ, Huang, MT, Sharkansky, EJ, and Wolfe, J. Posttraumatic stress disorder and retrospectively reported stressor exposure: A longitudinal prediction model. Journal of Abnormal Psychology 2000; 109(4):624-633. (VA-7)

The Boston Environmental Hazards Research Center has been following 2,949 Army veterans who processed through Fort Devens, Massachusetts, at the time of their return from the Gulf War in 1991. (Wolfe, et al 1996) These veterans have been evaluated at four time points, starting within five days of their return to the U.S., and again at 18 to 24 months (Time 2), four years (Time 3), and six years (Time 4). The study population includes about 72% Reserve/National Guard and about 28% active duty, and it includes 84 units with a wide range of military occupational specialties from several regions of the U.S. At Time 2, 2,313 subjects participated, which was 78% of the original cohort.

The objective of this particular analysis was to use longitudinal data to evaluate risk factors for posttraumatic stress disorder (PTSD) over time. (King, et al, 2000) Comparisons were made at Time 1 and Time 2, focusing on responses on the Mississippi Scale for Combat-Related PTSD, a well-validated survey instrument. The Laufer

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Combat Exposure Scale, a validated questionnaire, was used to measure combat stressor exposure. It was supplemented by additional questions intended to represent events unique to the Gulf War, for a total of 31 combat stressors. This analysis examined the association between PTSD and retrospective self-reports of exposure to highly stressful events. In particular, it focused on the question: To what extent does PTSD symptom severity alter later reports of stressor exposure?

Mean scores on both the reported stressor measure and the PTSD scale increased between Time 1 and Time 2. On the reported stressor measure, only 9% of the subjects responded completely consistently at Time 1 and Time 2. The mean number of changes was 3 out of 31 questions. The number of no-to-yes changes was two times the number of yes-to-no changes, which means that persons who initially disavowed a particular exposure later endorsed that event. Some questions changed by as much as 30% over time. This is puzzling, since some of these exposures were serious, dramatic, and distressing events, such as Did you see Americans or other troops killed or wounded?

The number of changes in the stressor measure had a significant, although small, association with the severity of PTSD symptoms at both Time 1 and Time 2. One possible explanation is that increased reporting as a function of PTSD symptoms might be related to efforts to explain distress in terms of prior war experiences; veterans experiencing psychological problems might seek justification by increasing their endorsement of possible causal events. However, there was little evidence that the severity of Time 1 PTSD symptoms significantly influenced reporting of stressor exposure at Time 2. Stressor exposures reported at Time 2 were primarily related to stressor exposures reported at Time 1. The authors concluded that changes in reporting past events over time should not necessarily be a source of undue alarm that Time 1 PTSD symptom severity accounts for those changes.

4. Sharkansky, EJ, King, DW, King, LA, Wolfe, J, Erickson, DJ, and Stokes, LR. Coping with Gulf War combat stress: mediating and moderating effects. Journal of Abnormal Psychology 2000; 109(2):188-197. (VA-7)

The Boston Environmental Hazards Research Center has been performing a prospective study of 2,949 Army veterans since their return from the Gulf War in 1991. (Wolfe, et al, 1996; King, et al, 2000) The objective of this particular analysis was to evaluate the relationship between psychological symptoms at Time 1 and Time 2 and different types of strategies for coping with combat-related stress. (Sharkansky, et al, 2000) The hypothesis was that greater reliance on avoidance-based coping would be associated with worse outcomes (higher levels of symptoms of PTSD and depression). Coping is defined as conscious efforts to manage internal or external stressors that the individual perceives as exceeding existing resources. In previous studies, efforts to deal directly with the stressor (problem-focused or approach-based coping) tended to be associated with better outcomes, compared to attempts to alleviate the emotional distress associated with the stressor or efforts to avoid the stressor (emotion-focused or avoidance-based coping).

1,058 subjects (36% of the total cohort at Time 1) were selected for this analysis. These subjects were selected because they had identified a combat-related experience as their most stressful event during the Gulf War (for example, a SCUD missile attack or deaths of unit members). They were asked to identify which of 48 possible coping strategies they used to deal with the most stressful event. PTSD and depression symptoms were assessed with two validated questionnaires, the Mississippi Scale for Combat-Related PTSD and the Brief Symptom Inventory.

At Time 1, increased PTSD symptoms were predicted by combat exposure (number of combat-related stressors), female gender, younger age, Reserve/National Guard status, and enlisted status. PTSD symptoms at Time 1 were also predicted by proportionately greater reliance on avoidance-based coping strategies during the war. At Time 2, PTSD symptoms were predicted by PTSD symptoms at Time 1, combat exposure, Reserve/National Guard status, and intervening stressors (such as divorce or loss of a home due to a disaster, between Time 1 and Time 2). PTSD symptoms at Time 2 were not predicted by coping strategies during the war. At Time 1, depression symptoms were predicted by combat exposure, female gender, and proportionately greater reliance on avoidance-based coping strategies during the war. At Time 2, depression symptoms were predicted by

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combat exposure, intervening stressors, and proportionately greater reliance on avoidance-based coping strategies during the war.

The authors concluded: These data suggest that soldiers who actively attempt to cope with combat-related stress by analyzing and making efforts to solve the problem, seeking guidance and support from others, and positively reappraising the situation fared better initially and in the long run than those who coped by avoiding thinking about the situation, getting involved with distracting activities, letting off emotional steam, or resigning themselves to the situation. They stated their data suggested the potential value of training military personnel in more active methods of coping with war zone stress to aid in the prevention of some combat-related disorders.

5. Benotsch, EG, Brailey, K, Vasterling, JJ, Uddo, M, Constans, JI, and Sutker, PB. War zone stress, personal and environmental resources, and PTSD symptoms in Gulf War veterans: a longitudinal perspective. Journal of Abnormal Psychology 2000; 109(2):205-213. (VA-12)

The New Orleans Veterans Affairs Medical Center has been following 348 Gulf War veterans since 1991, including 180 members of the Louisiana National Guard and 168 members of the Army, Marine, Air Force, or Navy Reserve. (Sutker, et al, 1995; Brailey, et al, 1998) The initial assessments occurred an average of 14 months after the end of hostilities (Time 1). Follow-up assessments occurred an average of 13 months later (Time 2). The assessments were identical at both time points. The 348 participants available for retesting were from an original sample of 828 (42% response at Time 2). Attrition was due to reservists having left the military, having been transferred to another unit, or being absent from drill exercises on the scheduled retest date. Although there did not appear to be important psychological differences between the participants who were retested and